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Multivariate methods in the development of a new tablet formulation: optimization and validation
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Research Group for Chemometrics)
Pharmacia AB, Consumer Healthcare, Helsingborg, Sweden.
Pharmacia AB, Consumer Healthcare, Helsingborg, Sweden.
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2004 (English)In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 30, no 10, 1037-1049 p.Article in journal (Refereed) Published
Abstract [en]

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.

Place, publisher, year, edition, pages
New York: M. Dekker , 2004. Vol. 30, no 10, 1037-1049 p.
Keyword [en]
Multivariate design, Validation, Disintegration time, PCA, PLS
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-3958DOI: 10.1081/DDC-200040243OAI: oai:DiVA.org:umu-3958DiVA: diva2:142879
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Multivariate methods in tablet formulation
Open this publication in new window or tab >>Multivariate methods in tablet formulation
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the application of multivariate methods in a novel approach to the formulation of tablets for direct compression. It begins with a brief historical review, followed by a basic introduction to key aspects of tablet formulation and multivariate data analysis. The bulk of the thesis is concerned with the novel approach, in which excipients were characterised in terms of multiple physical or (in most cases) spectral variables. By applying Principal Component Analysis (PCA) the descriptive variables are summarized into a few latent variables, usually termed scores or principal properties (PP’s). In this way the number of descriptive variables is dramatically reduced and the excipients are described by orthogonal continuous variables. This means that the PP’s can be used as ordinary variables in a statistical experimental design. The combination of latent variables and experimental design is termed multivariate design or experimental design in PP’s. Using multivariate design many excipients can be included in screening experiments with relatively few experiments.

The outcome of experiments designed to evaluate the effects of differences in excipient composition of formulations for direct compression is, of course, tablets with various properties. Once these properties, e.g. disintegration time and tensile strength, have been determined with standardised tests, quantitative relationships between descriptive variables and tablet properties can be established using Partial Least Squares Projections to Latent Structures (PLS) analysis. The obtained models can then be used for different purposes, depending on the objective of the research, such as evaluating the influence of the constituents of the formulation or optimisation of a certain tablet property.

Several examples of applications of the described methods are presented. Except in the first study, in which the feasibility of this approach was first tested, the disintegration time of the tablets has been studied more carefully than other responses. Additional experiments have been performed in order to obtain a specific disintegration time. Studies of mixtures of excipients with the same primary function have also been performed to obtain certain PP’s. Such mixture experiments also provide a straightforward approach to additional experiments where an interesting area of the PP space can be studied in more detail. The robustness of a formulation with respect to normal batch-to-batch variability has also been studied.

The presented approach to tablet formulation offers several interesting alternatives, for both planning and evaluating experiments.

Place, publisher, year, edition, pages
Umeå: Kemi, 2004. 56 p.
Keyword
Organic chemistry, PCA, statistical experimental design, multivariate design, PLS, excipients, direct compression, tablet formulation, robustness testing, Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-268 (URN)91-7305-653-7 (ISBN)
Public defence
2004-05-28, KB3B1, KBC, Linneaus väg, Umeå, 09:00
Opponent
Supervisors
Available from: 2004-05-07 Created: 2004-05-07 Last updated: 2011-03-10Bibliographically approved

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